Pathological reactive aggression is a condition characterized by frequent outbursts of impulsive violence and anger. The devastating socio-economic impact of this problem underscores the urgent need to identify effective strategies for its prevention and treatment; unfortunately, current efforts in this direction are thwarted by our poor knowledge of the pathophysiology of reactive aggression. The long-term goal of our research is to elucidate the neurobiological bases of aggression, and identify novel molecular targets for the prevention and therapy of this complex condition. Animal models are indispensable tools to understand the mechanisms of aggression and test novel therapies, but their translational and predictive validity is often compromised by their failure to accurately reproduce the mechanisms of pathological aggression in humans. Thanks to our previous NIH R21 grant, we began to address this problem by developing the first mouse model of the best-characterized interaction of genetic and environmental vulnerability factors for pathological reactive aggression. This interaction involves: i) low activity of monoamine oxidase (MAO) A, the major enzyme for the metabolism of serotonin (5HT); ii) child neglect or abuse. To simulate this interaction, we generated a novel line of mice with low MAOA activity (MAOANeo), and subjected them to maternal separation (MS, simulating child neglect) during the first week of life. Similarly to the clinical scenario, MS induced high levels of aggression in adolescent and adult MAOANeo mice, but not in their wild-type littermates. Our preliminary data suggest that MS predisposes MAOANeo mice to develop aggression through the interplay of age-specific processes: 1) the activation of 5HT2A receptors during the first week of life; 2) progressive, age- dependent deficits of N-methyl-D-aspartate glutamate receptors (NMDARs) in the prefrontal cortex (PFC) throughout adolescence; and 3) the disinhibition of glutamatergic subcortical connections in adulthood. Based on these data, we hypothesize that the interaction of low MAOA activity and MS produces 5HT2A receptor overstimulation and age-dependent NMDAR alterations in the PFC. In turn, these PFC deficits lead to aggression through the disinhibition of downstream glutamate pathways across subcortical regions. We will test this hypothesis in three specific aims: in Aim 1, we will determine how the interaction of low MAO A activity and MS leads to early 5HT 2A receptor overstimulation; in Aim 2, we will examine how early 5HT2A receptor overstimulation leads to age-specific deficits of NMDAR signaling pathways in the PFC; in Aim 3, we will identify the subcortical regions that mediate the role of glutamate in the aggressive responses of MAOANeo mice subjected to MS. These aims will be accomplished with a unique combination of cutting-edge behavioral, neurochemical and proteomic technologies. The results of these translational studies will help us understand the biological bases of reactive aggression, identify new potential biomarkers and therapeutic targets for this condition, and eventually reduce its staggering socio-economic burden.